Major depressive disorder (MOD) is the fourth leading cause of disease burden worldwide, and the incidence of MOD in women is twice that of men. Thus understanding its etiology will have important implications for attenuation of disease burden, particularly in women. In this translational SCOR integrating scientists from basic and clinical fields in three Projects, we address the question of why women are at twice the risk for MOD than men. We hypothesize that sex differences in MOD are initiated during fetal development, during hypothalamic-pituitary-adrenal (HPA) circuitry development and the sexual differentiation of the brain, and a period in which fetal risk factors for MOD have been identified. The overall SCOR will test hypotheses regarding the roles of adrenal and gonadal signaling pathways regulating brain-derived nerve growth factor (BDNF;associated with MOD) and its interactions with gamma aminobutyric acid (GABA)-ergic, glutamate (GLU)-tamatergic and nitric oxide (NO) mechanisms in development of key brain regions in stress response circuitry. In Project 1, specific aims are to test for contributions of genetic polymorphisms associated with these pathways and maternal serum assessment of HPA abnormalities during mid-gestation to understanding sex differences in MOD. We identified 500 DSM-IV MOD cases and 500 normal controls from a birth cohort (followed from prenatal development to age 47) in which DMA has been stored and biosamples indicating maternal-fetal HPA-placental stress at mid-gestation will be evaluated. We will test for specific genetic polymorphisms associated with HPA circuitry development and MOD (cortiocotropin releasing hormone (CRH), BDNF, GABA, GLU, neuronal NO (nNOS), estrogen receptors (ER)a and p, and arginine vasopressin (AVP)). Mid-gestational physiologic stress will be operationalized as: abnormal levels of maternal-fetal hormones during mid-gestation indicative of stress (CRH, dehydroepiandrosterone-sulfate (DHEA-S), human chorionic gonadotropin (hCG), and bioactive androgens);and high levels of pro- inflammatory cytokines (interleukine (IL)-1p, IL-6 &tumor necrosis factor (TNF)-a) during mid-gestation. In addition 40 recurrent MOD cases, equally divided by gender, and 40 individually-matched normal controls from this birth cohort will be re-recruited for functional and structural brain imaging of stress response circuitry and neuroendocrine evaluations to test our hypotheses relating abnormal maternal-fetal HPA environment and genetic polymorphisms with sex differences in adult HPA axis dysfunction and functional brain activity deficits in stress response circuitry. We predict hormonal dysfunction will mediate sex differences in brain activity deficits in MOD, which will be associated with maternal-fetal HPA abnormalities. An understanding of the fetal mechanisms associated with sex differences in MOD will have etiologic imolications and imoortance for the development of sex-specific treatments and prevention of MOD.